肿瘤发展和治疗容忍度是高度调控且复杂的过程，主要依赖于癌细胞的可塑性和其对应激的反应能力。癌细胞的较高可塑性凸显了寻找可靶向分子途径来挑战癌细胞存活的必要性。在这里，我们展示了tRNA的N7-鸟嘌呤甲基化（m7G），由METTL1介导，调控了癌细胞对应激条件下的存活。从机制上讲，我们发现tRNA中的m7G保护它们免受应激引起的切割和加工成为5' tRNA片段的损害。我们的分析揭示了tRNA m7G甲基化丧失会激活应激反应途径，使癌细胞对应激更敏感。此外，我们发现METTL1的丧失会降低肿瘤生长并在体内增加细胞毒性应激。我们的研究揭示了tRNA的m7G甲基化在应激反应中的作用，并突出了靶向METTL1以增强癌细胞对化疗的潜力。© 2023. 作者。

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that N7-guanosine methylation (m7G) of tRNAs, mediated by METTL1, regulates survival to stress conditions in cancer cells. Mechanistically, we find that m7G in tRNAs protects them from stress-induced cleavage and processing into 5' tRNA fragments. Our analyses reveal that the loss of tRNA m7G methylation activates stress response pathways, sensitising cancer cells to stress. Furthermore, we find that the loss of METTL1 reduces tumour growth and increases cytotoxic stress in vivo. Our study uncovers the role of m7G methylation of tRNAs in stress responses and highlights the potential of targeting METTL1 to sensitise cancer cells to chemotherapy.© 2023. The Author(s).